A Potential 3-in-1 Combined Anti-SARS-CoV-2 Therapy Using Pulmonary MIL-100(Fe) Formulation
Exploration of a Novel Pulmonary Anti-SARS-CoV-2 Therapy Based on MIL-100(Fe)
In recent years, global public health has faced numerous severe challenges, particularly since 2019 with the outbreak of the SARS-CoV-2 coronavirus pandemic. The high transmission rate and persistence of the virus have exposed bottlenecks in current prevention and treatment approaches. This situation highlights the urgent need for more efficient and innovative therapies to combat future global infectious disease outbreaks. Against this backdrop, the emergence of nanomedicine offers alternatives to traditional methods. The design of nanocarriers holds the potential to improve drug stability, optimize distribution, and pharmacokinetics, thereby enhancing therapeutic efficacy and minimizing side effects. However, despite the significant promise that Metal–Organic Frameworks (MOFs) have shown in treating diseases like cancer and infections, their application as potential antiviral therapeutic platforms remains in its infancy. To address this gap, this study proposes a multi-functional pulmonary formulation based on MIL-100(Fe) nanoparticles with a “3-in-1” combined effect to explore their potential in combating SARS-CoV-2.
Research Origin and Background
This paper was authored by Beatrice Fodor and other scientists from the Advanced Porous Materials Unit at IMDEA Energy, Spain, in collaboration with renowned institutions such as Universidad Autónoma de Madrid and Université Montpellier. It was published in the Advanced Healthcare Materials journal and officially released by Wiley-VCH in 2025.
The research team explores MOFs as novel drug delivery system (DDS) platforms with potential biomedical applications. Specific attention is given to enhancing MOF efficacy in antiviral therapies and examining their potential for clinical translation. The study aims to develop a comprehensive treatment strategy for SARS-CoV-2 lung infections by integrating MIL-100(Fe) nanoparticles’ intrinsic properties with external drug and functional molecular modifications, delivering a “3-in-1” synergistic antiviral therapy.
Research Workflow
1. Nanoparticle Design and Synthesis
The first step was to design an optimized multi-functional MOF nanoparticle (MIL-100(Fe)). MIL-100(Fe) consists of a framework of trimesic acid ligands (H3BTC) coordinated with iron (Fe). Using a microwave-assisted synthesis method, a mixture of trimesic acid and ferric chloride hexahydrate (FeCl3·6H2O) aqueous solution was reacted at 130°C to form the crystalline structure. After synthesis, comprehensive analyses using techniques such as dynamic light scattering (DLS), X-ray powder diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, and Brunauer–Emmett–Teller (BET) surface area analysis were carried out to characterize the nanoparticle’s properties, including size, surface charge, and porosity.
Subsequently, the team coated the surface of MIL-100(Fe) with heparin (a functional polysaccharide with immune-modulatory and pathogen adhesion-inhibitory activity) via a facile solution impregnation method. This functional component significantly contributes to the platform’s therapeutic efficacy against SARS-CoV-2 infection. The antiviral drug Favipiravir (FVP) was then encapsulated within MIL-100(Fe)’s porous structure, substantially enhancing drug loading and usage efficiency. The final formulation, MIL-100(Fe)-Hep/FVP, integrates “immune modulation,” “virus inhibition,” and “drug release.”
Finally, using a spray-drying technique, the nanoparticles were combined with D-mannitol to form spherical particles of approximately 3 μm in diameter, resulting in a dry powder formulation suitable for pulmonary delivery for the next stage of in vivo experiments.
2. Evaluation Using an In Vitro SARS-CoV-2 Infection Model
In the in vitro experiments, recombinant human lung adenocarcinoma cells expressing the ACE2 receptor (A549-ACE2) were used as the infection model and exposed to live SARS-CoV-2 for 48 hours. Viral resistance was assessed indirectly through changes in SARS-CoV-2 nucleoprotein-N expression levels, while MTT dye and DAPI nuclear staining techniques were employed to evaluate the cells’ viability and confirm biocompatibility.
The experiments showed that the final FVP@MIL-100(Fe)-Hep formulation demonstrated superior antiviral effects. Compared to plain MIL-100(Fe), this formulation significantly reduced viral activity even at lower concentrations (inhibition rate increased from 5.8% to 38.4%). Furthermore, synergistic effects from the heparin coating and antiviral drug led to substantial infection suppression and excellent cell tolerance.
3. In Vivo Pulmonary Delivery and Distribution Studies
Targeting the lungs as the organ affected by COVID-19, the researchers further evaluated the powder formulation’s in vivo biodistribution and safety through intratracheal delivery in mice. Different groups were tested: Ma-FVP@MIL-100(Fe)-Hep, Ma-MIL-100(Fe), and a control group (air injection). Distribution across the lungs and other organs (liver, spleen) was tracked at multiple time points (0.5 h, 4 h, 24 h).
Key findings included: 1. Compared to the uncoated sample, the heparin-coated particles achieved significantly higher initial lung retention rates (16.3% vs. 5% at 0.5 hours). 2. While primarily cleared through the liver, the particles’ initial retention contributed to deep pulmonary delivery. 3. The heparin modification markedly reduced the early macrophage recognition and clearance, demonstrating its immune-evasion capabilities.
In toxicity studies, no significant inflammation or morphological damage was detected either in histological observations or behavioral assessments, further supporting the system’s biocompatibility.
4. Immune Response Evaluation
The study also analyzed immune response modulation by monitoring eight serum cytokines (e.g., IL-6, IL-12p70, TNF-α) in mice. The pulmonary platform significantly downregulated pro-inflammatory cytokine expression (e.g., IL-6 reduced by over one order of magnitude) while markedly upregulating anti-inflammatory cytokines like IL-10. These results suggest that the inclusion of heparin effectively shifts the immune response toward an anti-inflammatory profile without inducing severe inflammation.
Research Significance and Implications
This study innovatively combines MOFs with heparin and the validated antiviral drug Favipiravir to offer a novel therapeutic strategy for COVID-19 and similar pulmonary viral infections. Key highlights are as follows: 1. It reveals the intrinsic antiviral activity of the MIL-100(Fe) framework along with its non-toxic characteristics. 2. It demonstrates a breakthrough in immune regulation and deep lung delivery through heparin surface modifications. 3. It successfully develops a spray-dried microsphere formulation ready for pulmonary application, laying the groundwork for future clinical translation.
The study’s conclusions open new horizons for the use of MOFs in antiviral therapies, providing a practical solution for combating future global pandemics. This “3-in-1” platform may become a critical tool in the global fight against infectious diseases.